Date of Award

Fall 12-2017

Degree Type

Masters Thesis

Degree Name

Master of Science (MS)

Department

Biological Sciences

Committee Chair

Alex Flynt

Committee Chair Department

Biological Sciences

Committee Member 2

Fengwei Bai

Committee Member 2 Department

Biological Sciences

Committee Member 3

Shahid Karim

Committee Member 3 Department

Biological Sciences

Abstract

miRNAs are post-transcriptional regulators of gene expression, with numerous being involved in neurobiology. Within the human genome a quarter of the identified miRNA loci derive from a class of miRNAs termed tailed mirtrons. Despite the identification of this large population of miRNA, no functional studies have been conducted to identify their role. In this study we examined the highly expressed and deeply conserved Drosophila 3’ tail mirtron, miR-1017, as a candidate to elucidate tailed mirtron functionality. We identified acetylcholine receptor transcripts, Da5 and Da2, as bona fide targets for miR-1017. Interestingly, Da2 is also the host transcript for miR-1017. We utilized the GAL4/UAS system, to observe the miR-1017 expression pattern; furthermore we witnessed a disrupted feedback loop in the miR-1017 null background resulting in higher Da2 transcriptional activation. This could be phenocopied with the acetylcholine receptor (AchR) activity antagonist, Donepezil, which likewise resulted in higher GFP expression. Together this suggests that Da2 transcription is modulated by acetylcholine neurotransmission. Consistent with a role in dampening AchR activity miR-1017 mutant flies exhibit a neurodegeneration due to excitotoxicity. Ectopic expression of miR-1017 within an Alzhiemers disease fly model dampened the pathologenesis and improved neurological function and lifespan. Therefore revealing miR-1017, a 3’ tailed mirtron, as a significant neuroprotector within Drosophila. The coupled expression of Da2 and miR-1017 works as a negative feedback loop that limits activity dependent transcription of Da2.

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